One of the key mediators of cardiovascular risk in obesity is the development of hypertension. Obesity is the principal modifiable risk factor for hypertension, and one of the major contributors to its very high prevalence. Nonetheless, the mechanisms underlying the dysregulation of blood pressure in obesity are incompletely understood. An impaired ability to handle a salt load, or salt-sensitivity, is regarded as an important mechanism for obesity-related hypertension. Salt-sensitivity is determined by the balance of salt-retaining and salt-excreting systems. One of the best-studied salt-retaining systems is the renin-angiotensin-aldosterone system (RAAS). Excess RAAS activation in obesity is well-established. The principal counter-regulatory system to the RAAS is the natriuretic peptide (NP) system. The NPs are natriuretic and vasodilatory molecules produced by the heart in response to increased chamber stress. However, little is known regarding changes in the NP axis in obesity. In preliminary work, we have shown that obese individuals have decreased circulating NP concentrations, which reverse with weight loss. However, resting NP levels may not adequately reflect the ability of the NP axis to respond to stimuli, emphasizing the need for more detailed physiologic studies, under controlled salt conditions and with standardized assessment of the NP and RAAS axes, and related target organs (kidney, heart, and vasculature). We postulate that obesity promotes a state of relative "NP deficiency," which leads to impaired NP responses to salt loading, increased salt-sensitivity and elevated blood pressure. In Specific Aim 1, we will assess the NP and target organ responses to acute and chronic salt loading, in lean versus obese individuals. In Aim 2, we will examine the effect of weight loss on the NP and target organ responses to acute and chronic salt loading. The proposed research represents a systematic effort to build upon the investigators'prior clinical investigations into the novel interactions between the NP axis, obesity, and cardiometabolic risk. These studies have the potential to provide important insight into the causes of hypertension in obesity. Furthermore, because the NP system is easily accessible to pharmacologic manipulation, establishing that "NP deficiency" exists and defining its physiologic consequences could suggest novel approaches to the treatment and prevention of obesity-related cardiovascular disease. PUBLIC HEALTH RELEVANCE: The development of high blood pressure in obese individuals leads to substantial morbidity and mortality, but how obesity promotes high blood pressure is not well understood. The proposed research investigates the role of hormones produced by the heart in the regulation of blood pressure and responses to dietary salt, which could have important implications for behavioral and pharmacologic treatments to lower cardiovascular risk in obesity.